1. Technical Field
The invention relates to novel compounds and compositions comprising oxadiazole derivatives, and methods of using the same.
2. Description of Related Technology
The endogenous cholinergic neurotransmitter, acetylcholine (ACh), exerts its biological effect via two types of cholinergic receptors, the muscarinic acetylcholine receptors (mAChR) and the nicotinic acetylcholine receptors (nAChR). nAChRs are pentameric assemblies of subunits surrounding a central pore that gates the flux of Na+, K+ and Ca2+ ions. At least 16 subunit proteins, i.e. α2-α10, β1-β10, γ, δ and ε, have been identified in neuronal tissues. These subunits provide for a great variety of homomeric and heteromeric combinations that account for the diverse receptor subtypes. For example, functional neuronal nAChR or neuronal nicotinic receptor (NNR) assemblies can be homomeric, comprising α7 or α8 or α9 subunits, or heteromeric, usually with at least one subunit from the α group (α2, α3, α4, α6) and the remainder from the β group (β2, β4). In the central nervous system, α4β2-containing NNR and α7-containing NNR subtypes are the most widespread and mediate synaptic and, possibly, paracrine functions. These NNRs are expressed at high levels in areas involved with learning and memory, and play key roles in modulating neurotransmission in these regions. Reduced cholinergic activity and dysregulation of NNRs have been correlated with disease states involving cognitive deficits, progressive dementia, and epilepsy. Accordingly, these NNRs are implicated in a range of physiological and patho-physiological functions related to cognitive function, learning and memory, reward, motor control, arousal and analgesia (reviewed in Gopalakrishnan, M. et al., Ion channels—Ligand-gated. Comprehensive Medicinal Chemistry II, Edited by Triggle D. J. et al., Major Reference Works, Elsevier. Unit 2.22, pp 877-918, 2006).
Neuronal nicotinic receptors, especially α4β2 neuronal nicotinic acetylcholine receptors (nAChRs) have been targeted for pain and various central nervous system diseases. Antisense knockdown of the α4 subunit was found to decrease the analgesic effect of agonists (Bitner R S, et al., Brain Res. 871:66-74, 2000). Reduced antinociceptive responses to nicotine also is seen in α4 gene knockout animals (Marubio L M, et al., Nature 398:805-810, 1999). Both α4 and β2 nAChRs are responsible for mediating nicotinic analgesia at supraspinal responses and spinal sites (Decker, M W, et al, Curr Top Med Chem., 4: 369-384, 2004). Antinociceptive effects through α4β2 nAChRs are generally attributed to stimulation of brainstem monoaminergic transmission, particularly in the raphe (Cucchiaro G, et al., J Pharmacol Exp Ther. 313:389-394, 2005). However, α4β2 stimulation of GABAergic and glycinergic inhibitory transmission in the spinal cord also may contribute (Rashid M H, et al., Pain 125:125-135, 2006).
Central α3* nAChRs may contribute to nicotinic analgesia (Khan I M, et al., J Neurocytol. 33:543-556, 2004), but α3β4 ligands are of little interest because of likely autonomic side effects. Indeed, the goal has been to avoid α3* neuronal nicotinic receptor (NNR), as the dose-limiting emetic liability of nonselective compounds has been attributed to activation of α3 containing nAChRs. α3* nAChRs are expressed in the enteric nervous system as well as in other components of the peripheral and central nervous systems. Area postrema and nucleus tractus solitarius are brainstem nuclei thought to be involved in nausea and emesis. α3* nAChRs in the dorsal motor nucleus of the vagus and in nucleus tractus solitarius have been implicated in gastric and blood pressure responses to nicotine injected locally (Ferreira M, et al J. Pharmacol. Exp. Ther., 294:230-238, 2000).
Compounds with varying degrees of selectivity for α4β2 nAChRs over other nicotinic subtypes (α3, α7, α1-containing) have been discovered over the years. For example, ABT-594 (referred to as Compound A in this application) was efficacious across a number of rodent models of nociception including acute thermal, chemogenic, neuropathic, and visceral pain (Decker M W, et al., Expert Opinion on Investigational Drugs, 10:1819-1830, 2001). Available data suggest that ligands with selectivity for the α4β2 nAChRs over α3β4 efficacy is preferred for low adverse event profiles. In theory, the therapeutic index could be expanded by (a) reducing α3β4 activity or (b) increasing α4β2 efficacy without increasing α3β4 activity. The latter may be achieved by an α4β2 selective positive allosteric modulator (PAM) either alone or in combination with exogenous α4β2 agonist. Positive allosteric modulators can potentiate effects by enhancing the efficacy and or potency of agonists. Accordingly, an α4β2 selective positive allosteric modulator can selectively enhance effects at the preferred α4β2 nAChRs over other nAChR subtypes.
Initially known positive allosteric modulators of the α4β2 nAChRs have been nonselective and not very potent. For example, nefiracetam has been reported to potentiate α4β2 nAChR responses (Narahashi T, et al., Biol. Pharm. Bull., 27:1701-1706, 2004). More recently, subtype selective PAMs have been disclosed. Compounds like 3-(3-pyridin-3-yl-1,2,4-oxadiazol-5-yl)benzonitrile and others have been described with robust α4β2 PAM effects with little modulatory activity at other subtypes such as α3β4 (e.g., see WO 2006/114400, published Nov. 2, 2006).
Pain is an unmet medical need and the methods and possibilities for treatments of such indications are insufficient. Although continued efforts are being made to treat pain using nAChR agonists, robust efficacy in pain may be limited by the range of side effects associated with their use, albeit to differing degrees. In light of the significance of chronic pain and the limitations in their treatment, it would be beneficial to identify new methods of treating such disorders, particularly in a manner that reduces adverse ganglionic effects such as at the gastrointestinal systems (e.g. emesis). It would be particularly beneficial to identify compounds and compositions that offer an opportunity to wide the therapeutic window of nicotinic (nAChR) agonists in pain. Enhanced efficacy with nAChR ligands for the treatment of other central nervous system diseases such as cognitive and attention deficits is also desirable.